ALZHEIMERS DISEASE

BY:AISHWARYA SINGH 11408005 B.Tech GENETIC ENGINEERING S.R.M UNIVERSITY

INTRODUCTION
Alzheimers disease is a neurological brain disorder named after a German physician, Alois Alzheimer, who first described it in 1906. It is the most common form of dementia which destroys the brain cells slowly and prgressively , eventually interfereing with many aspects of brain functions. Memory loss is one of the most earliest symptoms which gradually leads to widespread loss of mental abilities due to which people depend on others for every aspect of their care. It is marked by plaques and neurofibrillary tangles in brain cells due to which the areas associated with the intellectual

HISTORICAL BACKGROUND
It was in 1901 that German psychiatrist Alois Alzheimer identified the first case of Alzheimer's disease in a fifty-year-old woman Auguste D. When she died in 1906 her brain was sent to him for examination and then it was in 1907 that he published his talk. The autopsy reveald the most serious form of dementia , almost one-third of the cortical cells had died off. In their place instead they found peculiar deeply stained fibrillary bundles that were closely packed to one another, and seemed to be remnants of degenerated cell bodies.

ANALYSIS OF BRAIN
There are three interconnected levels of human brain: The brain stem and cerebellum The limbic system The cerebral cortex

The brainstem controls heart beat and body temperature. Cerebellum controls body movements.
The limbic system controls emotions .It is also center to memory and learning.

The hippocampus, is active in converting information into long-term memory and in memory recall. Damage to the hippocampus or its nerve connections can cause amnesia.

The amygdala, is concerned with emotional memory. But damage to the amygdala can abolish an emotion-charged memory.

In Alzheimer's disease, brain cells die and neuronal connections wither in all parts of the brain, but especially in the hippocampus and the amygdala.

GENERAL SYMPTOMS OF ALZHEIMERS DISEASE Loss of abstract thinking Disorientation Lack of initiative Language problems Missplacing items Mood swings Personality changes Poor judgement

CLINICAL SYMPTOMS
Amyloid plaques: deposition of amyloid beta (A) in brain tissue. Neurofibrillary tangles: formation of neurofibrillary tangles by hyperphosphorylated of tau proteins.

Neuronal loss: loss of nerve cells.

Gliosis: Glial cells are non-neuronal cells . Astrocytes are nothing but relatively large glial cells. Gliosis is a proliferation of astrocytes in damaged areas of the central nervous system (CNS) which causes CNS injury. Cholinergic depletion: reduced synthesis of the acetylcholine. Shrinkage of brain: reduction in brain size
Microscopy image of neurofibrillary tangle, conformed by hyperphosphoryla ted tau protein

The role of amyloid plaques in Alzheimer's

Amyloid plaques are mostly made up of a protein called B-amyloid protein which is itself part of a much larger protein called APP (amyloid precursor protein). We do not know exactly what APP does. But we do know that APP is made in the cell, transported to the cell membrane and later broken down.
In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is thought to be important for neuronal growth, survival, and repair.

Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab.

Beta-amyloid is sticky so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain.

Neuronal Plaques in Alzheimers Disease

The role of Neurofibrillary tangles

These

are insoluble twisted fibers found inside the brain's

cells. These tangles consist primarily of a protein called tau, which forms part of a structure called a microtubule. The microtubule helps transport nutrients and other important substances from one part of the nerve cell to another. In people with Alzheimer's tau proteins cause abnormality through overactive enzymes resulting in the formation of neurofibrillary tangles. Neurofibrillary tangles result in the death of the cells.

SEVERITY OF THE DISEASE

Early dementia
Difficulties with language, executive functions, and execution of movements are more prominent than memory problems. Older memories are affected to a lesser degree than new memories. They find difficulty in writing or dressing but they are commonly unnoticed.

Moderate dementia
Patients are unable to perform most common activities of daily living. Speech difficulties become evident and reading and writing skills are also lost. The person may fail to recognise close relatives. Long-term memory becomes impaired.

Advanced dementia
During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.

1 2

1. Pre clinical AD 2. Mild AD 3. Severe AD

PREVALANCE OF THE DISEASE

In India percentage of Alzheimer patients is 4 per cent as compared to United States. In India, prevalence of dementia is 33.6 per 1000.

In India, Alzheimer's disease among 70- to 79-year olds is 4.4fold less than that of the United States. WHO says there are currently about 18 million people worldwide with Alzheimers disease, which will double by 2025 to 34 million.
Much of this increase will be due to the ageing population.

EMINENT PERSONALITIES WITH ALZHEIMERS

Ronald Reagan (1911-2004), 40th President of the United States

Charlton Heston (October 4, 1923 April 5, 2008) was an American actor of film

GENETIC BASIS OF THE DISEASE

The exact Genetic cause of of Alzheimer's disease is not known. Common forms of certain genes increase the risk of developing Alzheimer's disease. The best-studied gene is the one that encodes apolipoprotein E (apoE) (found on chromosome 19) , a protein that helps carry blood cholesterol . It is found in neurons and other supportive brain cells (called glia) of healthy brains. The apoE gene has three different forms (alleles) -- apoE2, apoE3, and apoE4. The apoE4 form of the gene has been associated with increased risk of Alzheimer's disease in most (but not all) populations studied. At least one copy of the E4 gene is found in 40% of patients with sporadic or late-onset Alzheimer's disease.

The more APOE e4 alleles one inherits, the lower the age of disease onset.
The relatively rare APOE e2 allele may protect some people against the disease: It seems to be associated with a lower risk for Alzheimer's and a later age of onset if the disease does develop. APOE e3 is the most common version found in the general population and may play a neutral role in Alzheimer's risk. APOE e4 increases the risk of developing Alzheimer's, but it does not cause the disease. The ways in which APOE e4 increases the likelihood of developing Alzheimer's are not known with certainty.

Some studies have found that Alzheimer's disease occurs more often among people who suffered significant traumatic head injuries earlier in life, particularly among those with the apoE 4 gene. Most researchers believe that APOE testing is useful for studying Alzheimer's disease risk in large groups of people but not for determining any one person's specific risk. Most experts believe that additional genes may influence the development of late-onset Alzheimers in some way. Researchers have identified variants of the SORL1, CLU, PICALM, and CR1 genes that may play a role in risk of late-onset Alzheimers

Studies have found that women have a higher risk for Alzheimer's disease than men.

The apparent increased frequency of Alzheimer's disease in women has led to considerable research about the role of estrogen in Alzheimer's disease. Recent studies suggest that estrogen should not be prescribed to post-menopausal women for the purpose of decreasing the risk of Alzheimer's disease.
Nonetheless, the role of estrogen in Alzheimer's disease remains an area of research focus.

DIAGNOSTICS
It is impossible to be certain about Alzheimers disease diagnosis unless a sample of brain tissue (a biopsy) or a postmortem examination of the brain reveals the presence the plaques tangles. However, with current testing methods, a skilled doctor can correctly diagnose Alzheimers disease in about 90% of cases without performing a biopsy.

Diagnosing Alzheimer's disease is a process of elimination. Doctors must rule out other natural causes, such as malnutrition or clinical depression. They check the thyroid, to rule out problems there.

In many cases, symptoms of depression can be mistaken for Alzheimer's and vice versa.

The following things may be used to help make a diagnosis of Alzheimer's disease:

Patient History
A history from the patient helps the doctor assess a person's past and current health situation.

Mini-Mental State Exam (Neuropsychological Testing)

A mini-mental state exam is a very brief test that the doctor can use to test a person's problem solving skills, attention span, counting skills and memory. It will give the doctor insight into whether there has been damage to different areas of the brain.

Chest X-ray An X-ray is a test in which an image of the body is created by using low doses of radiation. X-rays can be used to diagnose a wide range of conditions, from bronchitis to broken bones. This test may be used by the doctor to help rule out other disorders that may be causing symptoms similar to those of Alzheimer's disease.

Laboratory Tests
The most common are blood tests and urinalysis. Blood tests may also be used to look for the presence of a specific gene that has been identified as a risk factor for Alzheimer's disease. A urinalysis is a test in which a urine sample is evaluated to detect abnormalities, such as abnormal levels of sugar or protein.

CT Scan CT (computed tomography) scanning is a technique in which multiple X-rays of the body are taken from different angles in a very short period of time. These images are then fed into a computer, which creates a series of images that look like "slices" through the body. CT scans can show certain changes that are characteristic of Alzheimer's disease in its later stages. These changes include a reduction in the size of the brain, referred to as atrophy. Magnetic Resonance Imaging (MRI) Magnetic resonance imaging, usually called MRI, is a test that produces very clear pictures, or images, of the human body without using X-rays. Instead, MRI uses a large magnet, radio waves, and a computer to produce these images. MRI is beneficial in ruling out other causes of dementia, such as tumors or strokes. It also may help to show the structural and functional changes in the brain that are associated with Alzheimer's disease.

Electroencephalography (EEG)
Electroencephalography (EEG) is a medical technique that measures brain function by analyzing the electrical activity generated by the brain. This activity is measured through special electrodes applied to the scalp. EEG can be contributing to

Electrocardiogram (ECG) An electrocardiogram (ECG) is a recording of the heart's electrical activity. This activity is registered as a graph or series of wavy lines on a moving strip of paper. This gives the doctor important information about the heart. This test may be used by the doctor to help rule out other conditions that may be causing symptoms similar to those of Alzheimer's disease.

Single Photon Emission Computed Tomography (SPECT) Scan

SPECT is a technique for creating very clear, three-dimensional pictures of a major organ, such as the brain or heart. SPECT scans involve the injection of a very small amount of a radioactive substance. Energy from the radioactive substance in the body is detected by a special camera, which then takes the pictures. Positron Emission Tomography (PET) Scan

PET scanning is a three-dimensional imaging technique that allows a doctor to examine the heart, brain, or other internal organs. PET scans also can show how the organs are functioning. PET scans can show the difference in brain activity between a normal brain and one affected by Alzheimer's disease; it can also help differentiate Alzheimer's disease from other forms of dementia.

PET scan of normal brain

PET scan of Alzheimers disease brain

CAN BLOOD TEST DIAGNOSE ALZHEIMERS???

A new blood test for Alzheimer's disease is 96% accurate at identifying the disease and can perhaps detect it even before symptoms such as memory loss appear, says the test's developer. ''This is a simple test that has high accuracy and can be run from a single drop of blood," says Robert Nagele, founder of Durin Technologies Inc., the company that is developing the test

The research results on the new test are published online in PLoS ONE.

HOW IT WORKS.
Nagele's test looks for antibodies in the blood specific to the disease. Alzheimer's is believed to start up to 10 years or so before symptoms are noticeable. Brain cells die and when they die, they pop, they explode, like a water balloon breaking. The contents of those dying cells spill partially back into the blood. Body makes antibodies against the cell debris that happens to facilitate the cleanup of the cell debris.

Nagele's team looked at blood samples from 50 people with Alzheimer's disease and 40 without Overall, the tests identified 96% of those with Alzheimer's correctly. It correctly identified 92.5% of those who didn't have Alzheimer's.

THEY ARE PREFERRING BLOOD TEST DUE TO THE FOLLOWING THREE REASONS
Testing urine means testing something that has already broken down in the body. Cerebral spinal fluid tests require an invasive spinal tap. Blood is always the method of choice

TREATMENT
There is no cure for Alzheimer's disease and no treatment to reverse or halt its progression.

Health care providers may use medicines to help manage troubling symptoms of Alzheimer's disease, including depression, behavioral problems etc.

Doctor will determine the best treatment for the Alzheimers patient based on various factors, including:
The patients age, overall health, and medical history Extent of the disease The patients tolerance for specific medicines and therapies

DRUGS USED TO TREAT ALZHEIMERS

Cholinesterase inhibitors (Aricept, Cognex, Exelon, Razadyne) Cholinesterase inhibitors curb the breakdown of acetylcholine, a chemical in the brain important for memory and learning. These drugs may slow the progression of symptoms for about half of people taking them for a limited time, on average 6 to 12 months. Aricept is the only treatment approved by the FDA for all stages of Alzheimers disease: mild, moderate, and severe. It is available as tablets to swallow or tablets to dissolve in the mouth.

Cognex was the first of these drugs to be FDA approved, but it is used less commonly than the other medications.
Exelon is approved for use in mild to moderate Alzheimers dementia and is available as a skin patch, capsules, and liquid form. Razadyne (formerly Reminyl) is also approved for mild to moderate Alzheimers

Common side effects include diarrhea, vomiting, nausea, fatigue, insomnia, loss of appetite, and weight loss.

Namenda it is thought to play a protective role in the brain by regulating the activity of a brain chemical called glutamate. Glutamate plays a role in learning and memory. Brain cells in people with Alzheimers disease release too much glutamate. Namenda is the only drug for Alzheimers that works this way. It may improve mental function and performance of daily activities for some people.

Side effects of Namenda include tiredness, dizziness, confusion, constipation, and headache

USING SURGERY There is no surgical treatment for Alzheimer's disease at this time. USING GENE THERAPY A new gene therapy that was successful in treating memory problems in mice with Alzheimers disease (AD)was discovered by scientists. EphB2 is a molecule that acts as both a receptor and an enzyme. It is thought to be involved in memory problems of AD because it is a master regulator of neurotransmission and its brain levels are decreased in the disease. Reducing EphB2 levels in normal healthy mice disrupted neurotransmission and gave them memory problems similar to those seen in AD. The researchers conclude that depletion of EphB2 is important in amyloidb-induced neuronal dysfunction and that increasing EphB2 levels or function could be beneficial in Alzheimers disease

The findings, published, in Human Molecular Genetics suggests injecting extra parkin genes could clear the brain of the amyloid particles. In the current study, the researchers showed the parkin gene degrades the amyloid beta protein.

A mouse model mimicing the early stages of Alzheimer's disease was delivered an inactive HIV lentivirus into the motor cortex of the mouse brains. It caused amyloid plaque to form inside the neurons, but not outside the cells. The hypothesis is that once amyloid builds inside the cells, the neurons burst leading to amyloid protein clumping and plaque between the brain cells.
Injected with the parkin protein on one side of the brain, leaving the other untouched as a control. The team found the boosting the parkin gene cleared the brain of Alzheimer's producing plaque. In the study, the parkin gene cleared away enough amyloid beta plaque in the brain that the researchers say regaining memory might be possible even after damage has occurred.

USING STEM CELL..

In the study, published in the journal Stem Cells, researchers describe a new method of duplicating the neurons using human embryonic stem cells.

They transplanted the new cells into the brains of mice .

The results showed that the cells, known as basal forebrain cholinergic neurons, developed which help the hippocampus retrieve memories in the brain, an ability that is lost in early Alzheimers disease.

Once there, these cells formed new connections with the surrounding cells and began producing acetylcholine, just like normal brain cells.

SURVIVAL RATE
Once the onset of Alzheimer's has begun it will be present in the victim's life until he dies.

Alzheimer's patients may die from infections they obtain in the late stages of the disease.

People with Alzheimer's disease often live for years with the disease.

The duration of Alzheimer's disease from time of diagnosis can be 20 years or more. The average length of time from onset of symptoms is thought to be in the range of 4 to 8 years.

ORGANISATIONS
Alzheimers and Related disorders Society Of India (ARDSI) , Cochin , Kerala Memory Clinic at Asha Hospital, Hyderabad, Andhra Pradesh, India. Agrawal Hospital in Vasai. India, 2011. First such centre in the State, the two-storey Agarwal Hospital will take care of 250 patients at the cost of Rs 500 per day per patient ICRI (Institute Of Clinical Research ) , India Trust Hospital in New Delhi, India (Alzheimer's Stem Cell Therapy is available) Alzheimer's Association , United States of America

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